The olfactory epithelium (OE) is one of the few tissues in adult animals that retains the remarkable ability to produce new neurons throughout the lifetime of the animal. This continual neuronal production is highly regulated and permits the replacement of olfactory sensory neurons (OSNs) that reach the end of their limited lifespan. Selective ablation of the entire mature OSN population induces proliferation of multipotent progenitors in the basal epithelium and the rapid replenishment of the depleted neuronal cells. These observations suggest a model in which mature neurons negatively regulate proliferation, and the loss of this neuron-derived feedback signal promotes the repopulation of the neuronal repertoire. GDF11, a member of the TGF-beta superfamily, is a strong candidate as a factor that neurons secrete to inhibit proliferation. This was discovered in studies examining its effects on proliferating OSN cell cultures, and a genetic mouse model in which it was knocked out. These observations were limited to embryonic tissue, because GDF11 knockout mice have defects in the development of multiple organ systems, rendering them inviable after birth. However, to know what role this candidate is playing in the exquisitely regulated neurogenesis in adult OE, GDF11 must be studied in the adult. The proposed research will provide a comprehensive examination of the role that this and closely-related factors play in the adult OE. First, a variety of labeling studies will be employed to identify the specific cells that send and receive this signal throughout the lifetime of the animal. Two distinct genetically-modified mouse lines will also be generated by crossing existing lines that will allow investigation of this system in the adult. The first will be a conditional knockout, which will use cre-lox technology to eliminate GDF11 function exclusively in the OE, allowing the normal development of other organ systems. The second line will utilize the tet modulation system allowing us to induce expression of follistatin, a GDF11 antagonist, at any time in the life of the animal. In both of these models, we can examine how blocking this pathway will alter proliferation and cell type composition in the OE. These experiments can easily be expanded to investigate the well-known decline in olfaction with age, as evidence suggests this may be related to decreases in neurogenesis. RELEVANCE: An age-related decline in olfaction leads to a decrease in the quality of life in a high proportion of the elderly. Evidence suggests that this may be related to a decreased turnover of odorant detecting neurons. Understanding the signals that modify this turnover (and how they change with age) may help us identify the cause of this decline in olfaction, and may identify targets for preventing or treating it. [unreadable] [unreadable] [unreadable]